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Impact of High Altitude Therapy on Type‐2 Immune Responses In DR. TADECH BOONPIYATHAD (Orcid ID : 0000-0001-8690-7647) DR. GE TAN (Orcid ID : 0000-0003-0026-8739) MRS. MÜBECCEL AKDIS (Orcid ID : 0000-0002-9228-4594) Article type : Original Article: Basic and Translational Allergy Immunology Impact of High Altitude Therapy on Type-2 Immune Responses in Asthma Patients Tadech Boonpiyathad1,2,3, Gertruda Capova3,4, Hans-Werner Duchna3,4, Andrew L. Croxford5, Herve Farine5, Anita Dreher1,4, Martine Clozel5, Juliane Schreiber4, Petr Kubena4, Nonhlanhla Lunjani1,3, David Mirer1, Beate Rückert1, Pattraporn 1,3 1 5 1 Article Satitsuksanoa , Ge Tan , Peter M.A. Groenen , Mübeccel Akdis , Daniel S. Strasser5, Ellen D. Renner3,4,6, Cezmi A. Akdis1,3 1Swiss Institute of Allergy and Asthma Research, University of Zurich, Davos, Switzerland 2Department of Medicine, Phramongkutklao Hospital, Bangkok, Thailand 3Christine Kühne Center for Allergy Research and Education, Davos, Switzerland 4Hochgebirgsklinik Davos, Davos, Switzerland 5Drug Discovery, Idorsia Pharmaceuticals Ltd., Allschwil, Switzerland 6Chair and Institute of Enviromental Medicine – UNIKA-T, TU Munich and Helmholtz Zentrum Munich, Germany Corresponding author: Cezmi A. Akdis Swiss Institute of Allergy and Asthma Research, Obere Strasse 22, CH-7270, Davos Platz, Switzerland Email: [email protected] Tel.: +41 81 140 0848 Fax: +41 81 410 0840 This article has been accepted for publication and undergone full peer review but has not Accepted been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/all.13967 This article is protected by copyright. All rights reserved. Short title Immune response of asthma treatment in high altitude Abstract Background: Asthma patients present with distinct immunological profiles, with a predominance of type 2 endotype. The aim of this study was to investigate the impact of high altitude treatment on the clinical and immunological response in asthma. Methods: Twenty-six hospitalized asthma patients (9 eosinophilic allergic; EA, 9 non-eosinophilic allergic; NEA and 8 non-eosinophilic non-allergic; NN) and 9 healthy controls in high-altitude for 21 days were enrolled in the study. We assessed eosinophils, T cells, Tregs, and innate lymphoid cells (ILC) from peripheral blood Article using flow cytometry. Results: The number of eosinophils (both resting and activated) and CRTH2- expressing CD4+ and CD8+ T cells decreased significantly in EA patients after altitude treatment. The frequency of CRTH2+ Tregs as decreased significantly in all the asthma phenotypes as well as the frequency of ILC2 was significantly reduced in EA after altitude treatment. After 21 days of altitude therapy, CRTH2-expressing ILC2, CD4+ and CD8+ T cells and Treg cells showed attenuated responses to exogenous PGD2. Furthermore, PGD2 signaling via CRTH2 was found to diminish the suppressive function of CRTH2+ Tregs which partially normalized during high altitude treatment. Improved asthma control was particularly evident in allergic asthma patients and correlated with decreased frequencies of CRTH2+ Treg cells in EA patients. Serum IL-5 and IL-13 decreased during climate treatment in asthma patients with high baseline levels. Conclusions: Asthma treatment in high altitude reduced the type 2 immune response, corrected the increased CRTH2 expression and its dysregulated functions. Accepted This article is protected by copyright. All rights reserved. Keywords: Eosinophils, T cells, CRTH2, asthma phenotype, high altitude. Abbreviations CRTH2: Chemoattractant receptor homolog expressed on Th2 cells EA: Eosinophilic allergic asthma NEA: Non-eosinophilic allergic asthma NN: Non-eosinophilic non-allergic asthma PGD2: Prostaglandin D2 Th2: T helper 2 Tc: T cytotoxic Tregs: Regulatory T cells ILC: Innate lymphoid cells Article Introduction Subtypes of asthma defined by the type of inflammation and complex immune-regulatory networks open the opportunity for new pathway precision diagnosis and targeted-treatments (1, 2). Asthma management can be individualized not only depending on the severity of the disease, but more importantly on the phenotypic and endotypic characteristics of the patient. An asthma endotype is defined by a distinct pathophysiological mechanism, such as the type 2 endotype (3, 4). Allergic asthma is the most common asthma phenotype with an earlier onset (5- 7). Non-allergic or intrinsic asthma includes a subset of patients with asthma without allergic sensitization (8, 9). These patients show quite variable response to standard therapy (5). Eosinophilic asthma is defined as blood eosinophilia (>350 cells/µl), associated with tissue and sputum eosinophilia, thickening of the basement membrane zone and often by good response to inhaled corticosteroid therapy (10, 11). Improvements in the blood and tissue eosinophilia are associated with fewer exacerbations and lower health care costs (6). Particularly, CD69 expression on eosinophils is an indicator for eosinophil activation (12). It is expressed at a low level on unstimulated blood eosinophils and upregulated by interleukin (IL)-5 (7). Accepted This article is protected by copyright. All rights reserved. Chemoattractant receptor homolog expressed on Th2 cells (CRTH2) represents one of two functional prostaglandin D2 (PGD2) receptors. CRTH2 is expressed on various types of cells; eosinophils, Th2 cells, ILC2, basophils, CD8+ T cells, mast cells, macrophages, monocytes and dendritic cells (13, 14). The PGD2/CRTH2 axis has emerged into a potential pathophysiologic factor for allergy and asthma (15). In allergic asthma patients, the production of PGD2 is increased by allergen exposure (16). After an allergen challenge, the concentration of PGD2 is increased in bronchoalveolar lavage fluid, and its 9α, 11β-PGF2 metabolite is increased in plasma (17). PGD2 effects are mediated partially by prostaglandin D2 receptor 1 (DP1) which causes bronchoconstriction, vasodilation, increases in capillary permeability and mucus production (18). CRTH2 on immune cells is involved in the migration and activation of Th2 cells, eosinophils, basophils and ILC2, and with production of type 2 cytokines IL-4, IL-5 and IL-13 (19). Elevated levels of peripheral CD4+CRTH2+ T cells is a feature of severe allergic asthma (20). Article ILC2s and Th2 cells are a significant source of type 2 cytokines and play a role in eosinophilic inflammatory response, allergy and remodeling in asthma (21, 22). Increased circulating and sputum IL-5 and IL-13-producing ILC2s were detected in severe asthma compared to mild asthma patients (15). Furthermore, increased numbers of IL-5+ and IL-13+ ILC2s were found in sputum after allergen challenge in asthma patients (23). Moreover, increased frequency of IL-13-producing ILC2 were enhanced by PGD2 that was co-stimulated with IL-2, IL-25 and IL-33 in asthma patients. (24, 25). IL-13-expressing ILC2 and Th2 cells are also responsible for bronchial epithelial tight junction barrier leakiness in asthma patients (26, 27). Several studies have demonstrated the efficacy of altitude therapy in treating asthma patients. The hypothesis the effect of high-altitude treatment combines anti- inflammatory treatment as allergen avoidance, lower pressure, less stress, less particle exposure and exposure to sunshine stimulate vitamin D photosynthesis. High altitude treatment showed significantly decreased monocyte activation and CRTH2 expression on CD4+CD25+ T cell in asthmatic patients (28). In children with atopic dermatitis, high altitude treatment showed significant reductions in memory Tregs, transitional B cells and plasmablasts. Concomitant, increases in memory B cells, effector memory CD8+ T cells, central memory CD4+ T cells and CCR7+ Th2 cells were reported (29). However, detailed changes to the immunological landscape after Accepted altitude therapy has not been described in asthma patient subgroups. The present This article is protected by copyright. All rights reserved. study asesses the kinetics of immunological changes in different asthma phenotypes in response to treatment in high altitude with specific focus on the CRTH2 receptor and its functions on ILCs, CD4 and CD8 T cell subsets, Tregs and eosinophils during the treatment. Methods Subjects This observational study enrolled 29 adult inpatients (14 males, 15 females and average aged 53.3 years) with asthma at the Pulmonary Clinic, Hochgebirgsklinik, Davos, Switzerland (1560m above sea level). Patients had an average stay of 21 days in Davos. All patients came from low altitude locations and chose their 21 days stay in Davos in to receive high altitude treatment. Nine healthy Article control subjects (5 males and 4 females) who visited Davos for the first time were recruited in the study (Table S1). All patients were treated with short-acting inhaled beta-agonists for quick relief asthma symptoms and long-acting inhaled beta- agonists plus inhaled corticosteroid (Table S2). No systemic corticosteroid treatment was used in the study. All patients showed good compliance with their treatment and proper inhalation technique of inhaled medication. Medical history, physical examination, pulmonary function test, exhaled nitric oxide (FeNO2) measurement were performed during the first days of admission to the hospital. The patients received questionnaires on asthma control test (ACT) score (30). Lithium heparin-coagulated blood were collected from patients with asthma and healthy control subjects at
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